Benzoxazine derivatives and uses thereof

ABSTRACT

The present invention provides a compound of the formula:  
                 
 
a pharmaceutically acceptable salt or a prodrug thereof, where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R 9 , Y, Z 1 , m, n, and p are as defined herein. The present invention also provides compositions comprising, methods for using, and methods for preparing Compound of Formula I.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is entitled to the benefit of U.S. ProvisionalApplication No. 60/378,003, filed on May 13, 2002, the disclosure ofwhich is incorporated herein by reference.

FIELD OF THE INVENTION

This invention relates to benzoxazine derivatives, and associatedcompositions, methods for use as therapeutic agents, and methods ofpreparation thereof.

BACKGROUND OF THE INVENTION

The actions of the neurotransmitter 5-hydroxytryptamine (5-HT) as amajor modulatory neurotransmitter in the brain, are mediated through anumber of receptor families termed 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5,5-HT6, and 5-HT7. Based on a high level of 5-HT6 receptor mRNA in thebrain, it has been stated that the 5-HT6 receptor may play a role in thepathology and treatment of central nerve system disorders. Inparticular, 5-HT6 selective ligands have been identified as potentiallyuseful in the treatment of certain CNS disorders such as Parkinson'sdisease, Huntington's disease, anxiety, depression, manic depression,psychoses, epilepsy, obsessive compulsive disorders, migraine,Alzheimer's disease (enhancement of cognitive memory), sleep disorders,feeding disorders such as anorexia and bulimia, panic attacks, attentiondeficit hyperactivity disorder (ADHD), attention deficit disorder (ADD),withdrawal from drug abuse such as cocaine, ethanol, nicotine andbenzodiazepines, schizophrenia, and also disorders associated withspinal trauma and/or head injury such as hydrocephalus. Such compoundsare also expected to be of use in the treatment of certaingastrointestinal (GI) disorders such as functional bowel disorder. Seefor example, B. L. Roth et al., J. Pharmacol. Exp. Ther., 1994, 268,pages 1403-14120, D. R. Sibley et al., Mol. Pharmacol., 1993, 43,320-327, A. J. Sleight et al., Neurotransmission, 1995, 11, 1-5, and A.J. Sleight et al., Serotonin ID Research Alert, 1997, 2(3), 115-8.

While some 5-HT6 modulators have been disclosed, there continues to be aneed for compounds that are useful for modulating 5-HT6.

SUMMARY OF THE INVENTION

The present invention provides compounds of the formula:

a pharmaceutically acceptable salt or a prodrug thereof,where

-   -   m is an integer from 0 to 3;    -   each of n and p is independently 2 or 3;    -   Y is —SO₂— or —SO₂N(R¹⁰)—, where R¹⁰ is hydrogen or lower alkyl;    -   Z¹ is CH or N;    -   each of R¹ and R² is independently hydrogen or alkyl, or R¹ and        R² together with the carbon to which they are attached may form        a carbocyclic group with 3 to 6 ring atoms;    -   R³ is alkyl, aryl, haloalkyl, heterocyclyl, or heteroaryl;    -   each R⁴ is independently halo, alkyl, haloalkyl, alkoxy, cyano,        —SO₂R^(a), —C(═O)NR^(b)R^(c), —SO₂—NR^(b)R^(c), —SR^(b),        —N(R^(b))—C(═OR^(c), —C(═O)R^(b), or —N(R^(b))—SO₂R^(a),    -    where        -   each R^(a) is independently alkyl or haloalkyl, and        -   each of R^(b) and R^(c) is independently hydrogen, alkyl, or            haloalkyl,    -   each of R⁵, R⁶, R⁷, and R⁸ is independently hydrogen or alkyl;        and    -   R⁹ is hydrogen, alkyl cycloalkyl, cycloalkylalkyl or benzyl; or        R⁹ and one of R⁵, R⁶, R⁷, or R⁸ together with the atoms to which        they are attached form a heterocycloamino ring with 5 to 7 ring        atoms.

The present invention also provides methods for preparing, compositionscomprising, and methods for using Compounds of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

Unless otherwise stated, the following terms used in this Application,including the specification and claims, have the definitions givenbelow. It must be noted that, as used in the specification and theappended claims, the singular forms “a”, “an,” and “the” include pluralreferents unless the context clearly dictates otherwise.

“Agonist” refers to a compound that enhances the activity of anothercompound or receptor site.

“Alkyl” means the monovalent linear or branched saturated hydrocarbonmoiety, consisting solely of carbon and hydrogen atoms, having from oneto twelve carbon atoms. “Lower alkyl” refers to an alkyl group of one tosix carbon atoms. Examples of alkyl groups include, but are not limitedto, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.

“Alkylene” means a linear saturated divalent hydrocarbon radical of oneto six carbon atoms or a branched saturated divalent hydrocarbon radicalof three to six carbon atoms, e.g., methylene, ethylene,2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene,and the like.

“Alkoxy” means a moiety of the formula R^(z), wherein R^(z) is an alkylmoiety as defined herein. Examples of alkoxy moieties include, but arenot limited to, methoxy, ethoxy, isopropoxy, and the like.

“Antagonist” refers to a compound that diminishes or prevents the actionof another compound or receptor site.

“Aryl” means a monovalent cyclic aromatic hydrocarbon moiety consistingof a mono- or bicyclic aromatic ring. The aryl group can optionally besubstituted with one, two or three, preferably one or two, substituents,wherein each substituent is independently hydroxy, cyano, alkyl, alkoxy,thiol, thioalkyl, halo, haloalkyl, nitro, amino, monoalkylamino,dialkylamino, piperazinyl or piperidinyl, unless otherwise specificallyindicated. Examples of aryl moieties include, but are not limited to,optionally substituted phenyl and optionally substituted naphthyl; andthe like.

“Cycloalkyl” means a monovalent saturated carbocyclic moiety consistingof mono- or bicyclic rings. Cycloalkyl can optionally be substitutedwith one or more substituents, wherein each substituent is independentlyhydroxy, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, ordialkylamino, unless otherwise specifically indicated. Examples ofcycloalkyl moieties include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

“Cycloalkylalkyl” means a moiety of the formula —R′—R″, where R′ isalkylene and R″ is cycloalkyl as defined herein.

“Disease state” means any disease, condition, symptom, or indication.

The terms “halo” and “halogen” are used interchangeably herein and referto a substituent fluoro, chloro, bromo, or iodo, preferably fluoro orchloro.

“Haloalkyl” means alkyl as defined herein in which one or more hydrogenhas been replaced with same or different halogen. Exemplary haloalkylsinclude —CH₂Cl, CH₂CF₃, —CH₂CCl₃, perfluoroalkyl (e.g., —CF₃), and thelike.

“Heteroaryl” means a monocyclic or bicyclic radical of 5 to 12 ringatoms having at least one aromatic ring containing one, two, or threering heteroatoms selected from N, O, or S, the remaining ring atomsbeing C, with the understanding that the attachment point of theheteroaryl radical will be on an aromatic ring. Heteroaryl canoptionally be substituted with one, two, or three, preferably, one ortwo, substituents, wherein each substituent is independently hydroxy,cyano, alkyl, alkoxy, thioalkyl, halo, haloalkyl, hydroxyalkyl,alkoxycarbonyl, amino, alkylamino, dialkylamino, aminocarbonyl,piperazinyl, piperidinyl or carbonylamino, unless otherwise specificallyindicated. Examples of heteroaryl moieties include, but are not limitedto, imidazolyl, oxazolyl, thiazolyl, pyrazinyl, thiophenyl, furanyl,pyranyl, pyridinyl, quinolinyl, isoquinolinyl, benzofuryl,benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzooxazolyl,benzooxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl,isoindolyl, and the like.

“Heterocycloamino” means a saturated ring wherein at least one ring atomis N, NH or N-alkyl and the remaining ring atoms form an alkylene group.

“Heterocyclyl” means a monovalent saturated moiety, consisting of one tothree rings, incorporating one, two, or three heteroatoms (chosen fromnitrogen, oxygen or sulfur). Heterocyclyl can optionally be substitutedwith one, two, or three, preferably one or two, substituents, whereineach substituent is independently hydroxy, alkyl, alkoxy, thioalkyl,halo, haloalkyl, hydroxyalkyl, alkoxycarbonyl, amino, alkylamino,dialkylamino, aminocarbonyl, or carbonylamino, unless otherwisespecifically indicated. Examples of heterocyclic moieties include, butare not limited to, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl,tetrahydropyranyl, and the like.

“Leaving group” means the group with the meaning conventionallyassociated with it in synthetic organic chemistry, i.e., an atom orgroup displaceable under substitution reaction conditions. Examples ofleaving groups include, but are not limited to, halogen, alkane- orarylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy,thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy,dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy,acyloxy, and the like.

“Modulator” means a molecule that interacts with a target. Theinteractions include, but are not limited to, agonist, antagonist, andthe like, as defined herein.

“Optional” or “optionally” means that the subsequently described eventor circumstance may but need not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not.

“Inert organic solvent” or “inert solvent” means the solvent is inertunder the conditions of the reaction being described in conjunctiontherewith, including for example, benzene, toluene, acetonitrile,tetrahydrofuran, N,N-dimethylformamide, chloroform, methylene chlorideor dichloromethane, dichloroethane, diethyl ether, ethyl acetate,acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol,tert-butanol, dioxane, pyridine, and the like. Unless specified to thecontrary, the solvents used in the reactions of the present inventionare inert solvents.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic, andneither biologically nor otherwise undesirable and includes that whichis acceptable for veterinary as well as human pharmaceutical use.

“Pharmaceutically acceptable salts” of a compound means salts that arepharmaceutically acceptable, as defined herein, and that possess thedesired pharmacological activity of the parent compound. Such saltsinclude:

-   -   acid addition salts formed with inorganic acids such as        hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,        phosphoric acid, and the like; or formed with organic acids such        as acetic acid, benzenesulfonic acid, benzoic, camphorsulfonic        acid, citric acid, ethanesulfonic acid, fumaric acid,        glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid,        hydroxynaphtoic acid, 2-hydroxyethanesulfonic acid, lactic acid,        maleic acid, malic acid, malonic acid, mandelic acid,        methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid,        propionic acid, salicylic acid, succinic acid, tartaric acid,        p-toluenesulfonic acid, trimethylacetic acid, and the like; or    -   salts formed when an acidic proton present in the parent        compound either is replaced by a metal ion, e.g., an alkali        metal ion, an alkaline earth ion, or an aluminum ion; or        coordinates with an organic or inorganic base. Acceptable        organic bases include diethanolamine, ethanolamine,        N-methylglucamine, triethanolamine, tromethamine, and the like.        Acceptable inorganic bases include aluminum hydroxide, calcium        hydroxide, potassium hydroxide, sodium carbonate and sodium        hydroxide.

The preferred pharmaceutically acceptable salts are the salts formedfrom acetic acid, hydrochloric acid, sulfuric acid, methanesulfonicacid, maleic acid, phosphoric acid, tartaric acid, citric acid, sodium,potassium, calcium, zinc, and magnesium.

It should be understood that all references to pharmaceuticallyacceptable salts include solvent addition forms (solvates) or crystalforms (polymorphs) as defined herein, of the same acid addition salt.

“Prodrug” or “pro-drug” means a pharmacologically inactive form of acompound which must be metabolized in vivo, e.g., by biological fluidsor enzymes, by a subject after administration into a pharmacologicallyactive form of the compound in order to produce the desiredpharmacological effect. The prodrug can be metabolized beforeabsorption, during absorption, after absorption, or at a specific site.Although metabolism occurs for many compounds primarily in the liver,almost all other tissues and organs, especially the lung, are able tocarry out varying degrees of metabolism. Prodrug forms of compounds maybe utilized, for example, to improve bioavailability, improve subjectacceptability such as by masking or reducing unpleasant characteristicssuch as bitter taste or gastrointestinal irritability, alter solubilitysuch as for intravenous use, provide for prolonged or sustained releaseor delivery, improve ease of formulation, or provide site-specificdelivery of the compound. Reference to a compound herein includesprodrug forms of a compound.

“Protective group” or “protecting group” means the group whichselectively blocks one reactive site in a multifunctional compound suchthat a chemical reaction can be carried out selectively at anotherunprotected reactive site in the meaning conventionally associated withit in synthetic chemistry. Certain processes of this invention rely uponthe protective groups to block reactive nitrogen and/or oxygen atomspresent in the reactants. For example, the terms “amino-protectinggroup” and “nitrogen protecting group” are used interchangeably hereinand refer to those organic groups intended to protect the nitrogen atomagainst undesirable reactions during synthetic procedures. Exemplarynitrogen protecting groups include, but are not limited to,trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl(carbobenzyloxy, CBZ), p-methoxybenzyloxycarbonyl,p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), and the like. Theartisan in the art will know how to chose a group for the ease ofremoval and for the ability to withstand the following reactions.

“Solvates” means solvent additions forms that contain eitherstoichiometric or non stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate, when the solvent is alcohol, thesolvate formed is an alcoholate. Hydrates are formed by the combinationof one or more molecules of water with one of the substances in whichthe water retains its molecular state as H₂O, such combination beingable to form one or more hydrate.

“Subject” means mammals and non-mammals. Mammals means any member of themammalia class including, but not limited to, humans; non-human primatessuch as chimpanzees and other apes and monkey species; farm animals suchas cattle, horses, sheep, goats, and swine; domestic animals such asrabbits, dogs, and cats; laboratory animals including rodents, such asrats, mice, and guinea pigs; and the like. Examples of non-mammalsinclude, but are not limited to, birds, and the like. The term “subject”does not denote a particular age or sex.

“Therapeutically effective amount” means an amount of a compound that,when administered to a subject for treating a disease state, issufficient to effect such treatment for the disease state. The“therapeutically effective amount” will vary depending on the compound,disease state being treated, the severity or the disease treated, theage and relative health of the subject, the route and form ofadministration, the judgement of the attending medical or veterinarypractitioner, and other factors.

The terms “those defined above” and “those defined herein” whenreferring to a variable incorporates by reference the broad definitionof the variable as well as preferred, more preferred and most preferreddefinitions, if any.

“Treating” or “treatment” of a disease state includes:

-   -   (i) preventing the disease state, i.e. causing the clinical        symptoms of the disease state not to develop in a subject that        may be exposed to or predisposed to the disease state, but does        not yet experience or display symptoms of the disease state.    -   (ii) inhibiting the disease state, i.e., arresting the        development of the disease state or its clinical symptoms, or    -   (iii) relieving the disease state, i.e., causing temporary or        permanent regression of the disease state or its clinical        symptoms.

The terms “treating”, “contacting” and “reacting” when referring to achemical reaction means adding or mixing two or more reagents underappropriate conditions to produce the indicated and/or the desiredproduct. It should be appreciated that the reaction which produces theindicated and/or the desired product may not necessarily result directlyfrom the combination of two reagents which were initially added, i.e.,there may be one or more intermediates which are produced in the mixturewhich ultimately leads to the formation of the indicated and/or thedesired product.

Nomenclature and Structures

In general, the nomenclature used in this Application is based onAUTONOM™ v.4.0, a Beilstein Institute computerized system for thegeneration of IUPAC systematic nomenclature. Chemical structures shownherein were prepared using ISIS® v. 2.2. Any open valency on a carbon,nitrogen or oxygen atom on the chemical structures herein should beunderstood as indicating the presence of a hydrogen.

Compounds of the Invention

In one aspect, the present invention provides a compound of the formula:

a pharmaceutically acceptable salt or a prodrug thereof,

-   -   wherein        -   m is an integer from 0 to 3; preferably, m is 0 or 1;        -   n is 2 or 3; preferably n is 2;        -   p is 2 or 3; preferably p is 2;        -   Y is —S(O₂) or —S(O₂)—N(R¹⁰), where R¹⁰ is hydrogen or lower            alkyl;            -   preferably, Y is —SO₂—;        -   Z¹ is CH or N; preferably Z¹ is N;        -   each of R¹ and R² is independently hydrogen or alkyl, or R¹            and R² together with the carbon to which they are attached            may form a carbocyclic group with 3 to 6 ring atoms;            preferably, R¹ and R² are hydrogen;        -   R³ is alkyl, aryl, haloalkyl, heterocyclyl, or heteroaryl;            preferably, R³ is aryl or heteroaryl;        -   each R⁴ is independently halo, alkyl, haloalkyl, alkoxy,            cyano, —SO₂R², —C(═O)—NR^(b)R^(c), —SO₂—NR^(b)R^(c),            —SR^(b), —N(R^(b))—C(═O)—R^(c), —C(═O)—R^(b), or            —N(R^(b))—SO₂—R^(a),        -    where            -   each R^(a) is independently alkyl or haloalkyl, and            -   each of R^(b) and R^(c) is independently hydrogen,                alkyl, or haloalkyl;        -   preferably each R⁴ is independently alkyl or halide; more            preferably each R⁴ is independently chloro or methyl;        -   each of R⁵, R⁶, R⁷, and R⁸ is independently hydrogen or            alkyl or;        -   preferably R⁵, R⁶, R⁷, and R⁸ are hydrogen; and R⁹ is            hydrogen, alkyl, cycloalkyl, cycloalkylalkyl or benzyl; or            R⁹ and one of R⁵, R⁶, R⁷, or R⁸ together with the atoms to            which they are attached form a heterocycloamino ring with 5            to 7 ring atoms; preferably, R⁹ is hydrogen or alkyl; more            preferably, R⁹ is hydrogen.

It is to be understood that the scope of this invention encompasses notonly the various isomers which may exist but also the various mixture ofisomers which may be formed. Furthermore, the scope of the presentinvention also encompasses solvates and salts of Compounds of Formula I.

In one embodiment, Compounds of Formula I are of the formula:

where R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, m, n, p, and Y are thosedefined herein.

In yet one embodiment, Compounds of Formula I are of the formula:

where R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, m, n, p, and Y are thosedefined herein. More specifically, where n is 2, p is 2, Y is S(O₂) andR¹, R², R⁵, R⁶, R⁷ and R⁸ are hydrogen, compounds of Formula I may berepresented by the formula:

where R³ and R⁹ are as defined herein.

In one particular embodiment, R³ is aryl. Preferably, R³ is optionallysubstituted phenyl or optionally substituted naphthyl. More preferably,R³ is phenyl, 2-fluorophenyl, 2-chlorophenyl, 3,4-dichlorophenyl,4-chlorophenyl, 3-chlorophenyl, 4-methoxyphenyl, 3,5-dichlorophenyl,2,6-dichlorophenyl, 2,4-dichlorophenyl, 3-methanesulfonylaminophenyl,2-methanesulfonylphenyl, 2-carbamoylphenyl, 3-methanesulfonylphenyl,4-methanesulfonylphenyl, 3-fluorophenyl, naphthyl, 2,4-difluorophenyl,2-cyanophenyl, 2-chloro-4-fluorophenyl, 2-methyl-5-fluorophenyl, or5-chloronaphthyl.

In another specific embodiment, R³ is preferably phenyl orhalo-substituted phenyl. More preferably, R³ is phenyl,2-chloro-substituted phenyl or 2-fluoro-substituted phenyl.

Yet in another embodiment, R³ is heteroaryl. Preferably, R³ isoptionally substituted isoquinolinyl, optionally substituted quinolinyl,optionally substituted thiophenyl, optionally substitutedbenzothiadiazolyl, optionally substituted imidazolyl, or optionallysubstituted benzoxadiazolyl. More preferably, R³ is quinolin-8-yl,2-thiophenyl, 5-chlorothiophen-2-yl, isoquinolin-5-yl,benzo[1,2,5]thiadiazol-4-yl, 1-methyl-1H-imidazol-4-yl, orbenzo[1,2,5]oxadiazol-4-yl.

Still further, combinations of the preferred groups described hereinwill form other preferred embodiments. For example, in one particularlypreferred embodiment Z¹ is N, m is 1, n is 2, p is 2, R³ is2-chlorophenyl, Y is —SO₂—, R⁴ is chloro, and R⁵, R⁶, R⁷, and R⁸ arehydrogen. In this manner, a variety of preferred compounds are embodiedwithin the present invention.

Some of the representative Compounds of Formula I are shown in Table 1below: TABLE 1 No. Name (Autonom ®) Structure 14-Benzenesulfonyl-6-methyl-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

2 4-(2-Chloro-benzenesulfonyl)-6-methyl-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

3 4-(3,4-Dichloro-benzenesulfonyl)-6-methyl-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

4 4-(4-Chloro-benzenesulfonyl)-6-methyl-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

5 4-(4-Chloro-benzenesulfonyl)-8-(3,5-dimethyl-piperazin-1-yl)-6-methyl-3,4-dihydro-2H- benzo[1,4]oxazine

6 6-Chloro-4-(2-chloro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

7 4-(3-Chloro-benzenesulfonyl)-6-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

8 4-(2-Chloro-benzenesulfonyl)-6-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

9 4-(2-Chloro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

10 4-(4-Chloro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

11 4-(4-Methoxy-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

12 8-Piperazin-1-yl-4-(quinoline-8-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine

13 4-(3,4-Dichloro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

14 4-(3-Chloro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

15 4-(3,5-Dichloro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

16 4-(2,3-Dichloro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

17 4-(2,6-Dichloro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

18 4-(2,4-Dichloro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

19 4-(4-Chloro-benzenesulfonyl)-6-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

20 N-[3-(8-Piperazin-1-yl-2,3-dihydro-benzo[1,4]oxazine-4-sulfonyl)-phenyl]- methanesulfonamide

21 N-[2-(8-Piperazin-1-yl-2,3-dihydro-benzo[1,4]oxazine-4-sulfonyl)-phenyl]- methanesulfonamide

22 2-(8-Piperazin-1-yl-2,3-dihydro-benzo[1,4]oxazine-4-sulfonyl)-benzamide

23 4-(3-Methanesulfonyl-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

24 6-Chloro-4-(4-methanesulfonyl-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H- benzo[1,4]oxazine

25 4-Benzenesulfonyl-8-piperazin-1-yl-3,4-dihydio- 2H-benzo[1,4]oxazine

26 4-(2-Fluoro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

27 4-(3-Fluoro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

28 4-Benzenesulfonyl-6-chloro-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

29 6-Chloro-4-(2-fluoro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

30 6-Chloro-4-(naphthalene-1-sulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

31 4-(2,3-Dichloro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

32 6-Chloro-8-piperazin-1-yl-4-(thiophene-2-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine

33 6-Chloro-8-piperazin-1-yl-4-(quinoline-8-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine

34 6-Chloro-4-(3-fluoro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

35 6-Chloro-4-(2,4-difluoro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

36 6-Chloro-4-(5-chloro-thiophene-2-Sulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

37 6-Chloro-4-(3-chloro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

38 6-Chloro-4-(2,3-dichloro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

39 2-(6-Chloro-8-piperazin-1-yl-2,3-dihydro-benzo[1,4]oxazine-4-sulfonyl)-benzonitrile

40 6-Chloro-4-(2-chloro-4-fluoro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

41 6-Chloro-4-(5-fluoro-2-methyl-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H- benzo[1,4]oxazine

42 6-Chloro-4-(5-chloro-naphthalene-1-sulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

43 6-Chloro-4-(isoquinoline-5-sulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

44 4-(Benzo[1,2,5]thiadiazole-4-sulfonyl)-6-chloro-8-piperazin-1-yl-3,4- dihydro-2H-benzo[1,4]oxazine

45 6-Chloro-4-(1-methyl-1H-imidazole-4-sulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

46 4-(Benzo[1,2,5]oxadiazole-4-sulfonyl)-6-chloro-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

47 4-(2-Fluoro-benzenesulfonyl)-6-methyl-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

48 2-(6-Methyl-8-piperazin-1-yl-2,3-dihydro-benzo[1,4]oxazine-4-sulfonyl)-benzonitrile

49 6-Methyl-8-piperazin-1-yl-4-(thiophene-2-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine

50 6-Methyl-8-piperazin-1-yl-4-(quinoline-8-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine

51 4-(3-Fluoro-benzenesulfonyl)-6-methyl-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

52 4-(2,4-Difluoro-benzenesulfonyl)-6-methyl-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

53 4-(2-Chloro-4-fluoro-benzenesulfonyl)-6-methyl-8-piperazin-1-yl-3,4-dihydro-2H- benzo[1,4]oxazine

54 4-(5-Fluoro-2-methyl-benzenesulfonyl)-6-methyl-8-piperazin-1-yl-3,4-dihydro-2H- benzo[1,4]oxazine

55 4-(Isoquinoline-5-sulfonyl)-6-methyl-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

56 6-Methyl-4-(1-methyl-1H-imidazole-4-sulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

57 4-(2-Fluoro-benzenesulfonyl)-6-methoxy-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

58 6-Chloro-4-(2-fluoro-benzenesulfonyl)-8-(4-methyl-piperazin-1-yl)-3,4-dihydro-2H- benzo[1,4]oxazine

59 6-Fluoro-4-(2-fluoro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

60 4-(3-Methanesulfonyl-benzenesulfonyl)-8-(4-methyl-piperazin-1-yl)-3,4-dihydro-2H- benzo[1,4]oxazine

61 6-Chloro-8-(4-methyl-piperazin-1-yl)-4-(naphthalene-2-sulfonyl)-3,4-dihydro-2H- benzo[1,4]oxazine

62 4-Benzenesulfonyl-8-(4-methyl-piperazin-1-yl)-3,4-dihydro-2H-benzo[1,4]oxazine

63 4-(2-Fluoro-benzenesulfonyl)-8-(4-methyl-piperazin-1-yl)-3,4-dihydro-2H-benzo[1,4]oxazine

64 4-Benzenesulfonyl-6-methoxy-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

65 4-Benzenesulfonyl-6-fluoro-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

66 2-(8-Piperazin-1-yl-2,3-dihydro- benzo[1,4]oxazine-4-sulfonyl)-phenol

67 4-(2-Methoxy-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

68 4-(2,3-Dihydro-benzo[1,4]dioxine-6-sulfonyl)-6-methoxy-8-piperazin-1-yl-3,4-dihydro-2H- benzo[1,4]oxazine

69 4-(2,3-Dihydro-benzo[1,4]dioxine-6-sulfonyl)-6-fluoro-8-piperazin-1-yl-3,4-dihydro-2H- benzo[1,4]oxazine

70 6-Methoxy-4-(naphthalene-1-sulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

71 4-(2-Chloro-benzenesulfonyl)-6-methoxy-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

72 4-(3-Chloro-benzenesulfonyl)-6-methoxy-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

73 4-(5-Fluoro-2-methyl-benzenesulfonyl)-6-methoxy-8-piperazin-1-yl-3,4-dihydro-2H- benzo[1,4]oxazine

74 6-Methoxy-8-piperazin-1-yl-4-(toluene-2-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine

75 2-(6-Methyl-8-piperazin-1-yl-2,3-dihydro-benzo[1,4]oxazine-4-sulfonyl)-phenol

76 6-tert-Butyl-4-(2-fluoro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]Oxazine

77 6-Piperazin-1-yl-4-(4-piperazin-1-yl-benzenesulfonyl)-3,4-dihydro-2H- benzo[1,4]oxazine

78 4-(3-Chloro-benzenesulfonyl)-8-[1,4]diazepan-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

79 4-(2-Fluoro-benzenesulfonyl)-2,2-dimethyl-8-piperazin-1-yl-3,4-dihydro- 2H-benzo[1,4]oxazine

80 9-Benzenesulfonyl-4-piperazin-1-yl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene

Another aspect of the present invention provides a compositioncomprising a therapeutically effective amount of a Compound of Formula Iand a pharmaceutically acceptable carrier.

Yet another aspect of the present invention provides a method fortreating a CNS disease state in a subject comprising administering tothe subject a therapeutically effective amount of a Compound of FormulaI. Preferably, the disease state comprises psychoses, schizophrenia,manic depressions, neurological disorders, memory disorders, attentiondeficit disorder, Parkinson's disease, amyotrophic lateral sclerosis,Alzheimer's disease and Huntington's disease.

Still another aspect of the present invention provides a method fortreating a disorder of the gastrointestinal tract in a subjectcomprising administering to the subject a therapeutically effectiveamount of a Compound of Formula I.

Another aspect of the present invention provides a method for producinga Compound of Formula I.

Synthesis

Compounds of the present invention can be made by a variety of methodsdepicted in the illustrative synthetic reaction schemes shown anddescribed below.

The starting materials and reagents used in preparing these compoundsgenerally are either available from commercial suppliers, such asAldrich Chemical Co., or are prepared by methods known to those skilledin the art following procedures set forth in references such as Fieserand Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York,1991, Volumes 1-15; Rodd's Chemistry of Carbon Compounds, ElsevierScience Publishers, 1989, Volumes 1-5 and Supplementals; and OrganicReactions, Wiley & Sons: New York, 1991, Volumes 140. The followingsynthetic reaction schemes are merely illustrative of some methods bywhich the compounds of the present invention can be synthesized, andvarious modifications to these synthetic reaction schemes can be madeand will be suggested to one skilled in the art having referred to thedisclosure contained in this Application.

The starting materials and the intermediates of the synthetic reactionschemes can be isolated and purified if desired using conventionaltechniques, including but not limited to, filtration, distillation,crystallization, chromatography, and the like. Such materials can becharacterized using conventional means, including physical constants andspectral data.

Unless specified to the contrary, the reactions described hereinpreferably are conducted under an inert atmosphere at atmosphericpressure at a reaction temperature range of from about −78° C. to about150° C., more preferably from about 0° C. to about 125° C., and mostpreferably and conveniently at about room (or ambient) temperature,e.g., about 20° C.

In one embodiment, Compounds of Formula I, where Z¹ is N, are preparedby a coupling reaction between an aryl halide of the formula:

and a heterocyclyl of the formula:

to produce a heterocyclyl-substituted phenyl of the formula:

where R¹, R², R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, m, n, and p are those definedherein; X¹ is a halide, preferably bromide; and R¹¹ is a nitrogenprotecting group, or —Y—R³ (where Y and R³ are those defined herein).

The coupling reaction between Compound of Formulas II and III istypically conducted in an inert organic solvent, such as toluene orxylene, in the presence of a coupling catalyst. Suitable couplingcatalysts include a mixture of a transition metal catalyst, such as apalladium source (e.g., tris(dibenzylideneacetone)palladium(0) andpalladium acetate), and a suitable phosphine ligand, such as2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, and tri-o-tolylphosphine.In some cases, a base is also added to the coupling reaction. Suitablebases include non-nucleophilic or sterically hindered bases, such ascarbonates, bicarbonates, and metal tert-butoxides (e.g., sodiumtert-butoxide and potassium tert-butoxide).

The coupling reaction between Compound of Formulas II and III generallyrequires elevated temperature, typically in the range of from about 50°C. to about 150° C. Preferably, the coupling reaction temperature rangeis from about 80° C. to about 110° C. More preferably, about 95° C.However, it should be appreciated that the coupling reaction temperatureis not limited to these ranges. The coupling reaction temperature canvary significantly depending on the nature of the substrate as well asother factors, such as the coupling catalyst, concentrations of eachcomponents, etc.

The reaction time for coupling Compound of Formulas II and III can alsovary widely depending on a variety of factors, such as those mentionedabove. Generally, the coupling reaction time ranges from about 5 hoursto 72 hours, preferably from about 8 hours to about 15 hours, with about12 hours being a typical coupling reaction time.

After the coupling reaction, the protecting group R¹¹ of Compound ofFormula IV is removed using conventional deprotection reactionconditions to produce a deprotected heterocyclyl-substituted phenyl ofthe formula:

Conditions for deprotecting Compound of Formula IV vary depending on thenature of the protecting group R¹¹. Suitable deprotection reactionconditions are well known to one skilled in the art. See, for example,Protective Groups in Organic Synthesis, 3^(rd) edition, T. W. Greene andP. G. M. Wuts, John Wiley & Sons, New York, 1999, which is incorporatedherein by reference in its entirety.

The deprotected heterocyclyl-substituted phenyl of Formula V is thencoupled with a compound of the formula: R³—Y—W, wherein W is anactivating group, to produce the Compound of Formula I. Suitableactivating groups, W, are well known to one skilled in the art. Forexample, when W is a sulfonyl group (SO₂), typical activating groupsinclude halides, preferably chloride.

Coupling conditions for reacting the deprotectedheterocyclyl-substituted phenyl of Formula V with the compound of theformula R³—Y—W can include a base. Suitable bases include weaklynucleophilic or non-nucleophilic bases, such as carbonates,bicarbonates, pyridine, and sterically hindered tertiary amine, andother bases known to one skilled in the art.

The reaction temperature ranges widely depending on a variety of factorsincluding the reactivity of reagents. Generally, the coupling reactiontemperature ranges from −78° C. to room temperature. Preferably, from−78° C. to about 0° C.

Alternatively, Compounds of Formula I can be prepared by reacting ahalogenated aryl of the formula:

with a compound of the formula: R³—Y—W to produce a halogenated phenylcompound of the formula:

Reaction conditions for coupling the Compound of Formula VI with theCompound of Formula R³—Y—W are similar to those described above forcoupling Compound of Formula V with the same activated coupling reagent.

The resulting halogenated phenyl Compound of Formula VII is then coupledwith a heterocyclyl compound of the formula:

in the presence of a coupling catalyst to produce the Compound ofFormula I. Such reaction conditions are similar to those described abovefor coupling the Compound of Formula II with the Compound of FormulaIII.

More specific details for producing Compounds of Formula I are describedin the Examples section.

Utility

The compounds of the invention have selective 5-HT6 receptor affinityand as such are expected to be useful in the treatment of certain CNSdisorders such as Parkinson's disease, Huntington's disease, anxiety,depression, manic depression, psychosis, epilepsy, obsessive compulsivedisorders, migraine, Alzheimer's disease (enhancement of cognitivememory), sleep disorders, feeding disorders such as anorexia andbulimia, panic attacks, attention deficit hyperactivity disorder (ADHD),attention deficit disorder (ADD), withdrawal from drug abuse such ascocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and alsodisorders associated with spinal trauma and/or head injury such ashydrocephalus. Such compounds are also expected to be of use in thetreatment of certain GI (gastrointestinal) disorders such functionalbowel disorder.

Testing

The pharmacology of the compounds of this invention was determined byart recognised procedures. The in vitro techniques for determining theaffinities of test compounds at the 5-HT6 receptor in radioligandbinding and functional assays are described in Example 4.

Administration and Pharmaceutical Composition

The present invention includes pharmaceutical compositions comprising atleast one compound of the present invention, or an individual isomer,racemic or non-racemic mixture of isomers or a pharmaceuticallyacceptable salt or solvate thereof, together with at least onepharmaceutically acceptable carrier, and optionally other therapeuticand/or prophylactic ingredients.

In general, the compounds of the present invention will be administeredin a therapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. Suitable dosageranges are typically 1-500 mg daily, preferably 1-100 mg daily, and mostpreferably 1-30 mg daily, depending upon numerous factors such as theseverity of the disease to be treated, the age and relative health ofthe subject, the potency of the compound used, the route and form ofadministration, the indication towards which the administration isdirected, and the preferences and experience of the medical practitionerinvolved. One of ordinary skill in the art of treating such diseaseswill be able, without undue experimentation and in reliance uponpersonal knowledge and the disclosure of this Application, to ascertaina therapeutically effective amount of the compounds of the presentinvention for a given disease.

In general, compounds of the present invention will be administered aspharmaceutical formulations including those suitable for oral (includingbuccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal, orparenteral (including intramuscular, intraarterial, intrathecal,subcutaneous and intravenous) administration or in a form suitable foradministration by inhalation or insufflation. The preferred manner ofadministration is generally oral using a convenient daily dosage regimenwhich can be adjusted according to the degree of affliction.

A compound or compounds of the present invention, together with one ormore conventional adjuvants, carriers, or diluents, may be placed intothe form of pharmaceutical compositions and unit dosages. Thepharmaceutical compositions and unit dosage forms may be comprised ofconventional ingredients in conventional proportions, with or withoutadditional active compounds or principles, and the unit dosage forms maycontain any suitable effective amount of the active ingredientcommensurate with the intended daily dosage range to be employed. Thepharmaceutical compositions may be employed as solids, such as tabletsor filled capsules, semisolids, powders, sustained release formulations,or liquids such as solutions, suspensions, emulsions, elixirs, or filledcapsules for oral use; or in the form of suppositories for rectal orvaginal administration; or in the form of sterile injectable solutionsfor parenteral use. Formulations containing about one (1) milligram ofactive ingredient or, more broadly, about 0.01 to about one hundred(100) milligrams, per tablet, are accordingly suitable representativeunit dosage forms.

The compounds of the present invention may be formulated in a widevariety of oral administration dosage forms. The pharmaceuticalcompositions and dosage forms may comprise a compound or compounds ofthe present invention or pharmaceutically acceptable salts thereof asthe active component. The pharmaceutically acceptable carriers may beeither solid or liquid. Solid form preparations include powders,tablets, pills, capsules, cachets, suppositories, and dispersiblegranules. A solid carrier may be one or more substances which may alsoact as diluents, flavouring agents, solubilizers, lubricants, suspendingagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material. In powders, the carrier generally is a finelydivided solid which is a mixture with the finely divided activecomponent. In tablets, the active component generally is mixed with thecarrier having the necessary binding capacity in suitable proportionsand compacted in the shape and size desired. The powders and tabletspreferably contain from about one (1) to about seventy (70) percent ofthe active compound. Suitable carriers include but are not limited tomagnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin,dextrin, starch, gelatine, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as carrier, providing acapsule in which the active component, with or without carriers, issurrounded by a carrier, which is in association with it. Similarly,cachets and lozenges are included. Tablets, powders, capsules, pills,cachets, and lozenges may be as solid forms suitable for oraladministration.

Other forms suitable for oral administration include liquid formpreparations including emulsions, syrups, elixirs, aqueous solutions,aqueous suspensions, or solid form preparations which are intended to beconverted shortly before use to liquid form preparations. Emulsions maybe prepared in solutions, for example, in aqueous propylene glycolsolutions or may contain emulsifying agents, for example, such aslecithin, sorbitan monooleate, or acacia Aqueous solutions can beprepared by dissolving the active component in water and adding suitablecolorants, flavors, stabilizers, and thickening agents. Aqueoussuspensions can be prepared by dispersing the finely divided activecomponent in water with viscous material, such as natural or syntheticgums, resins, methylcellulose, sodium carboxymethylcellulose, and otherwell known suspending agents. Solid form preparations include solutions,suspensions, and emulsions, and may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The compounds of the present invention may be formulated for parenteraladministration (e.g., by injection, for example bolus injection orcontinuous infusion) and may be presented in unit dose form in ampoules,pre-filled syringes, small volume infusion or in multi-dose containerswith an added preservative. The compositions may take such forms assuspensions, solutions, or emulsions in oily or aqueous vehicles, forexample solutions in aqueous polyethylene glycol. Examples of oily ornonaqueous carriers, diluents, solvents or vehicles include propyleneglycol, polyethylene glycol, vegetable oils (e.g., olive oil), andinjectable organic esters (e.g., ethyl oleate), and may containformulatory agents such as preserving, wetting, emulsifying orsuspending, stabilizing and/or dispersing agents. Alternatively, theactive ingredient may be in powder form, obtained by aseptic isolationof sterile solid or by lyophilization from solution for constitutionbefore use with a suitable vehicle, e.g., sterile, pyrogen-free water.

The compounds of the present invention may be formulated for topicaladministration to the epidermis as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also containing one or more emulsifying agents,stabilizing agents, dispersing agents, suspending agents, thickeningagents, or coloring agents. Formulations suitable for topicaladministration in the mouth include lozenges comprising active agents ina flavored base, usually sucrose and acacia or tragacanth; pastillescomprising the active ingredient in an inert base such as gelatine andglycerine or sucrose and acacia; and mouthwashes comprising the activeingredient in a suitable liquid carrier.

The compounds of the present invention may be formulated foradministration as suppositories. A low melting wax, such as a mixture offatty acid glycerides or cocoa butter is first melted and the activecomponent is dispersed homogeneously, for example, by stirring. Themolten homogeneous mixture is then poured into convenient sized molds,allowed to cool, and to solidify.

The compounds of the present invention may be formulated for vaginaladministration. Pessaries, tampons, creams, gels, pastes, foams orsprays containing in addition to the active ingredient such carriers asare known in the art to be appropriate.

The compounds of the present invention may be formulated for nasaladministration. The solutions or suspensions are applied directly to thenasal cavity by conventional means, for example, with a dropper, pipetteor spray. The formulations may be provided in a single or multidoseform. In the latter case of a dropper or pipette, this may be achievedby the patient administering an appropriate, predetermined volume of thesolution or suspension. In the case of a spray, this may be achieved forexample by means of a metering atomizing spray pump.

The compounds of the present invention may be formulated for aerosoladministration, particularly to the respiratory tract and includingintranasal administration. The compound will generally have a smallparticle size for example of the order of five (5) microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. The active ingredient is provided in a pressurizedpack with a suitable propellant such as a chlorofluorocarbon (CFC), forexample, dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, or carbon dioxide or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by a metered valve. Alternatively theactive ingredients may be provided in a form of a dry powder, forexample a powder mix of the compound in a suitable powder base such aslactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powder carrier will form agel in the nasal cavity. The powder composition may be presented in unitdose form for example in capsules or cartridges of e.g., gelatine orblister packs from which the powder may be administered by means of aninhaler.

When desired, formulations can be prepared with enteric coatings adaptedfor sustained or controlled release administration of the activeingredient. For example, the compounds of the present invention can beformulated in transdermal or subcutaneous drug delivery devices. Thesedelivery systems are advantageous when sustained release of the compoundis necessary and when patient compliance with a treatment regimen iscrucial. Compounds in transdermal delivery systems are frequentlyattached to an skin-adhesive solid support. The compound of interest canalso be combined with a penetration enhancer, e.g., Azone(1-dodecylazacycloheptan-2-one). Sustained release delivery systems areinserted subcutaneously into the subdermal layer by surgery orinjection. The subdermal implants encapsulate the compound in a lipidsoluble membrane, e.g., silicone rubber, or a biodegradable polymer,e.g., polylactic acid.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Other suitable pharmaceutical carriers and their formulations aredescribed in Remington: The Science and Practice of Pharmacy 1995,edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton,Pa. Representative pharmaceutical formulations containing a compound ofthe present invention are described in Examples 6-12.

EXAMPLES

The following preparations and examples are given to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof.

Example 1

This example illustrates a method for producing Compounds of Formula Iusing the synthetic scheme outlined below:

Method A: Synthesis of8-bromo-6-chloro-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic Acid BenzylEster

8-Bromo-6-chloro-2,3-dihydro-benzo[1,4]oxazine used in this Example wasprepared by first reacting 2-amino-6-bromo-4-chloro-phenol withchloroacetyl chloride to provide8-bromo-6-chloro-4H-benzo[1,4]oxazin-3-one using the procedure reportedby Combs et al.; J. Med. Chem.; 33; 380-386 1990. This benzoxazinone wasthen reduced to 8-bromo-6-chloro-2,3-dihydro-benzo[1,4]oxazine usingborane in THF according to the procedure described in Tetrahedron;53(26); 8853-8870 1997.

Benzyl chloroformate (1.877 g, 0.011 mol) was added dropwise to asolution of 8-bromo-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine (2.85 g,0.01 mol) in a 1:1 mixture of ethyl acetate (30 mL) and 10% aqueoussodium hydroxide (30 mL). After 3 hours at ambient temperature, thelayers were separated and the organic phase was washed with water (2×50mL), saturated aqueous sodium bicarbonate (50 mL), dried (K₂CO₃) andconcentrated in vacuo and the residue was purified by columnchromatography on silica gel (eluting with hexane-ethyl acetate; 7:3,V/V) to give 8-bromo-6-chloro-2,3-dihydro-benzo[1,4]oxazine-4-carboxylicacid benzyl ester as an oil (3.47 g, 98%). A sample was recrystallizedfrom ethanol-water. MS: MH⁺ 383. M.P. 95.0-97.7° C.

Similarly prepared were:

-   8-bromo-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid benzyl ester    (81%);-   8-bromo-6-methoxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid    benzyl ester;-   8-bromo-6-fluoro-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid    benzyl ester; and-   8-bromo-6-tert-butyl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid    benzyl ester.

Method B: Synthesis of8-bromo-6-methyl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic Acid BenzylEster

A solution of benzyl chloroformate (1.32 g, 0.008 mol) indichloromethane (20 mL) was added dropwise under nitrogen to an ice-coldsolution of 8-bromo-6-methyl-3,4-dihydro-2H-benzo[1,4]oxazine (1.78 g,0.007 mol) and pyridine (1.06 g, 0.013 mol) in dichlormethane (40 mL).After 1 hour at ambient temperature, a 10% aqueous HCl solution wasadded. The layers were separated and the organic phase was washed withwater (50 mL×2), dried (Na₂SO₄) and concentrated to give8-bromo-6-methyl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid benzylester as a colorless oil (2.34 g, 96%) which was used in the step 2without purification.

Synthesis of8-(4-tert-butoxycarbonyl-piperazin-1-yl)-6-chloro-2,3-dihydro-benzo[1,4]oxazine-4-carboxylicAcid

A three neck flask was charge with tris(dibenzylideneacetone)dipalladium(0) (21.5 mg, 0.024 mmol, 2 mol % Pd),(±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (36.4 mg, 0.059 mmol, 5mol %) and sodium-tert-butoxide (159 mg, 1.65 mmol) and flushed withnitrogen. A solution of8-bromo-6-chloro-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid benzylester (450 mmg, 1.18 mmol) and piperazine-1-carboxylic acid tert-butylester (263 mg, 1.41 mmol) in toluene (2 mL) was added. The mixture washeated to 95° C. and was stirred for 12 hours. The mixture was cooled toroom temperature, taken up in ethyl acetate, filtered through celite andconcentrated. The crude material was purified by flash chromatography onsilica gel (eluting with hexane-ethyl acetate; 7:3, v/v) to give8-(4-tert-butoxycarbonyl-piperazin-1-yl)-6-chloro-2,3-dihydro-benzo[1,4]oxazine-4-carboxylicacid benzyl ester a colorless oil (275 mg, 48%). MS: MH⁺=488.

Similarly, using the appropriately substitutedmethyl-3,4-dihydro-2H-benzo[1,4]oxazine the following compounds wereprepared.

-   8-(4-tert-Butoxycarbonyl-piperazin-1-yl)-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic    acid benzyl ester (66%);-   8-(4-tert-Butoxycarbonyl-piperazin-1-yl)-6-methyl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic    acid benzyl ester (58%);-   8-(4-tert-Butoxycarbonyl-piperazin-1-yl)-6-methoxy-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic    acid benzyl ester;-   8-(4-tert-Butoxycarbonyl-piperazin-1-yl)-6-fluoro-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic    acid benzyl ester; and-   8-(4-tert-Butoxycarbonyl-piperazin-1-yl)-6-tert-butyl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic    acid benzyl ester.

Method A: Synthesis of4-(6-chloro-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-piperazine-1-carboxylicAcid Tert-Butyl Ester (R¹=Cl)

A solution of8-(4-tert-butoxycarbonyl-piperazin-1-yl)-6-chloro-2,3-dihydro-benzo[1,4]oxazine-4-carboxylicacid benzyl ester (870 mg, 1.79 mmol) in ethanol (10 mL) washydrogenated at atmospheric pressure over 10% Pd/C (75 mg) for 0.5 hour.The catalyst was removed by filtration, and the filtrate wasconcentrated. The crude material was purified by flash chromatography onsilica gel (eluting with hexane-ethyl acetate; 1:1, v/v) to give4-(6-chloro-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-piperazine-1-carboxylicacid tert-butyl ester as a white foam (450 mg, 71%). MS: MH⁺=354.

Similarly the following compound was prepared

-   4-(3,4-Dihydro-2H-benzo[1,4]oxazin-8-yl)-piperazine-1-carboxylic    acid tert-butyl ester (95%). MS: MH⁺ 320.-   4-(6-Methyl-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-piperazine-1-carboxylic    acid tert-butyl ester (95%). MS: MH⁺ 334.

Method B: Synthesis of4-(3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-piperazine-1-carboxylic AcidTert-Butyl Ester (R¹=H)

A solution of8-(4-tert-butoxycarbonyl-piperazin-1-yl)-6-chloro-2,3-dihydro-benzo[1,4]oxazine-4-carboxylicacid benzyl ester (640 mg, 1.32 mmol) in ethanol (10 mL) washydrogenated at 50 psi in the presence of palladium on carbon for 12hours. The catalyst was removed by filtration, and the filtrate wasconcentrated to give4-(3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-piperazine-1-carboxylic acidtert-butyl ester as a light yellow solid (350 mg, 84%). MS: MH⁺=320.

Similarly prepared were:

-   4-(6-Methoxy-3,4-dihydro-2H-benzo    [1,4]oxazin-8-yl)-piperazine-1-carboxylic acid tert-butyl ester;-   4-(6-Fluoro-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-piperazine-1-carboxylic    acid tert-butyl ester; and-   4-(6-tert-Butyl-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-piperazine-1-carboxylic    acid tert-butyl ester.

Synthesis of6-chloro-4-(3-methanesulfonyl-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

3-Methanesulfonyl-benzenesulfonyl chloride (80 mg, 0.314 mmol) was addedin small portions under nitrogen to an ice-cold solution of4-(6-chloro-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-piperazine-1-carboxylicacid tert-butyl ester (101 mg, 0.285 mmol) and pyridine (50 mg, 0.628mmol) in dichlormethane (2 mL). After 1.5 hours at ambient temperature,water was added. The layers were separated and the organic phase waswashed with saturated aqueous solution of sodium bicarbonate (20 mL),dried (Na₂SO₄) and concentrated to give4-[6-chloro-4-(3-methanesulfonyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl]-piperazine-1-carboxylicacid tert-butyl ester as an oil (150 mg, 91%).

The crude material was dissolved in ethanol (1 mL) and was treated witha solution of 10% hydrogen chloride in ethanol (1 mL). The mixture washeated on a steam bath for 15 minutes. White crystals precipitated uponcooling to ambient temperature. The solid was collected, washed withcold ethanol. Drying under vacuum gave6-chloro-4-(3-methanesulfonyl-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,hydrochloride salt as a white powder (130 mg, 95%). MS: MH⁺=472. M.p.147.2-153° C.

Similarly, but replacing 3-methylsulfonyl-benzenesulfonyl chloride withthe appropriate arylsulfonyl chlorides followed by de-protection usingtrifluoracetic acid, the following compounds were prepared:

-   6-Chloro-4-(3-fluoro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    trifluoroacetic acid salt. MS: MH⁺=412.-   6-Chloro-4-(2,4-difluoro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    trifluoroacetic acid salt. MS: MH⁺=430.-   6-Chloro-4-(3-chloro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    trifluoroacetic acid salt. MS: MH⁺=419.-   6-Chloro-4-(2,3-dichloro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    trifluoroacetic acid salt. MS: MH⁺=463.-   6-Chloro-4-(2-chloro-3-fluoro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    trifluoroacetic acid salt. MS: MH⁺=447.-   6-Chloro-4-(4-fluoro-2-methyl-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    trifluoroacetic acid salt. MS: MH⁺=447.-   6-Chloro-4-(5-chloro-naphthalene-1-sulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    trifluoroacetic acid salt. MS: MH⁺=479.-   6-Chloro-8-piperazin-1-yl-4-(quinoline-8-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine,    trifluoroacetic acid salt. MS: MH⁺=445-   6-Chloro-4-(isoquinoline-5-sulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    trifluoroacetic acid salt. MS: MH⁺=445-   2-(6-Chloro-8-piperazin-1-yl-2,3-dihydro-benzo[1,4]oxazine-4-sulfonyl)-benzonitrile,    trifluoroacetic acid salt. MS: MH⁺=419.-   6-Chloro-8-piperazin-1-yl-4-(thiophene-2-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine,    trifluoroacetic acid salt.-   4-(Benzo[1,2,5]thiadiazole-4-sulfonyl)-6-chloro-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    trifluoroacetic acid salt. MS: MH⁺=452.-   6-Chloro-4-(1-methyl-1H-imidazole-4-sulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    trifluoroacetic acid salt. MS: MH⁺=398.-   6-Chloro-4-(5-chloro-thiophene-2-sulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    trifluoroacetic acid salt. MS: MH⁺=435.-   4-(Benzo[1,2,5]oxadiazole-4-sulfonyl)-6-chloro-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    trifluoroacetic acid salt. MS: MH⁺=436.

Similarly, but replacing piperazine-1-carboxylic acid tert-butyl esterin step 2 with N-methyl piperazine and using the appropriate aryl- orheteroaryl-chloride in step 4 followed by deprotection with HCl, thefollowing were prepared:

-   6-Chloro-8-(4-methyl-piperazin-1-yl)-4-(naphthalene-2-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine,    hydrochloride salt. MS: MH⁺=457.-   6-Chloro-4-(2-fluoro-benzenesulfonyl)-8-(4-methyl-piperazin-1-yl)-3,4-dihydro-2H-benzo[1,4]oxazine,    hydrochloride salt. MS: MH⁺=425.

Similarly, but replacing4-(6-chloro-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-piperazine-1-carboxylicacid tert-butyl ester with4-(3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-piperazine-1-carboxylic acidtert-butyl ester, and replacing 3-methylsulfonyl-benzenesulfonylchloride with the appropriate aryl- or heteroaryl-sulfonyl chloridesfollowed by de-protection using trifluoracetic acid or hot hydrogenchloride in ethanol, the following compounds were prepared:

-   4-(4-Chloro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    trifluoroacetic acid salt. MS: MH⁺=390.-   4-(3-Chloro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    trifluoroacetic acid salt. MS: MH⁺=390.-   4-(3,4-Dichloro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    trifluoroacetic acid salt. MS: MH⁺=429.-   4-(2,3-Dichloro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    trifluoroacetic acid salt. MS: MH⁺=429.-   4-(2,6-Dichloro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    trifluoroacetic acid salt. MS: MH⁺=429.-   4-(2,4-Dichloro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    trifluoroacetic acid salt. MS: MH⁺=429.-   4-(3,5-Dichloro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    trifluoroacetic acid salt. MS: MH⁺=429.-   4-(4-Methoxy-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    trifluoroacetic acid salt. MS: MH⁺=429.-   8-piperazin-1-yl-4-(quinoline-8-sulfonyl)-3,4-dihydro-2H-benzo    [1,4]oxazine, trifluoroacetic acid salt. MS: MH⁺=411.-   4-Benzenesulfonyl-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    hydrochloride salt as a white powder. MS: MH⁺=360. M.p. 235.8-239.5°    C.-   4-(2-Chloro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    hydrochloride salt as white powder. MS: MH⁺=390. M.p. 246.9-248.8°    C.-   4-(3-Fluoro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    hydrochloride salt as a white powder. MS: MH⁺=378. M.p. 186.6-187.9°    C.-   4-(2-Fluoro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    hydrochloride salt as a white powder. MS: MH⁺=378. M.p. 258.7-259.4°    C.-   4-(3-methanesulfonyl-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    hydrochloride salt as a white powder. MS: MH⁺=438. M.p. 193.9-203.8°    C.-   4-(2-methanesulfonyl-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    hydrochloride salt as a white powder. MS: MH⁺=438. M.p. 168.7-171.9°    C.-   4-(2,3-Dichloro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    hydrochloride salt as a white powder. MS: MH⁺=429. M.p. 266.9-271.9°    C.-   2-(8-piperazin-1-yl-2,3-dihydro-benzo[1,4]oxazine-4-sulfonyl)-phenol,    hydrochloride salt. MS: MH⁺ 374.-   4-(2-Methoxy-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    hydrochloride salt. MS: MH⁺ 388.-   6-piperazin-1-yl-4-(4-piperazin-1-yl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine,    hydrochloride salt. MS: MH⁺ 443.

Similarly, but replacing8-bromo-6-chloro-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid benzylester and piperazine-1-carboxylic acid tert-butyl ester in step 2respectively with 8-bromo-2,3-dihydro-benzo[1,4]oxazine-4-carboxylicacid benzyl ester and methyl piperazine, and subsequently using theappropriate arylsulfonyl chloride in step 4 followed by deprotection,the following were prepared:

-   4-(3-Methanesulfonyl-benzenesulfonyl)-8-(4-methyl-piperazin-1-yl)-3,4-dihydro-2H-benzo[1,4]oxazine,    hydrochloride salt. MS: MH⁺ 451.-   4-Benzenesulfonyl-8-(4-methyl-piperazin-1-yl)-3,4-dihydro-2H-benzo[1,4]oxazine,    hydrochloride salt. MS: MH⁺ 372.-   4-(2-Fluoro-benzenesulfonyl)-8-(4-methyl-piperazin-1-yl)-3,4-dihydro-2H-benzo[1,4]oxazine,    hydrochloride salt. MS: MH⁺ 390.

Similarly, but replacing4-(6-chloro-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-piperazine-1-carboxylicacid tert-butyl ester with4-(6-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-piperazine-1-carboxylicacid tert-butyl ester, and replacing 3-methylsulfonyl-benzenesulfonylchloride with the appropriate aryl- or heteroaryl-sulfonyl chloridesfollowed by de-protection using trifluoracetic acid or hot hydrogenchloride in ethanol, the following compounds were prepared:

-   4-(2-Fluoro-benzenesulfonyl)-6-methyl-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    trifluoroacetic acid salt, MS: MH⁺ 390.-   2-(6-Methyl-8-piperazin-1-yl-2,3-dihydro-benzo[1,4]oxazine-4-sulfonyl)-benzonitrile,    trifluoroacetic acid salt, MS: MH⁺ 397.-   6-Methyl-8-piperazin-1-yl-4-(thiophene-2-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine,    trifluoroacetic acid salt, MS: MH⁺ 379.-   6-Methyl-8-piperazin-1-yl-4-(quinoline-8-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine,    trifluoroacetic acid salt, MS: MH⁺ 424.-   4-(3-Fluoro-benzenesulfonyl)-6-methyl-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    trifluoroacetic acid salt, MS: MH⁺ 390.-   4-(2,4-Difluoro-benzenesulfonyl)-6-methyl-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    trifluoroacetic acid salt, MS: MH⁺ 408.-   4-(2-Chloro-4-fluoro-benzenesulfonyl)-6-methyl-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    trifluoroacetic acid salt, MS: MH⁺ 425.-   4-(5-Fluoro-2-methyl-benzenesulfonyl)-6-methyl-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    trifluoroacetic acid salt, MS: MH⁺ 404.-   4-(Isoquinoline-5-sulfonyl)-6-methyl-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    trifluoroacetic acid salt, MS: MH⁺ 424.-   6-Methyl-4-(1-methyl-1H-imidazole-4-sulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    trifluoroacetic acid salt, MS: MH⁺ 376.

Similarly, but replacing4-(6-chloro-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-piperazine-1-carboxylicacid tert-butyl ester with4-(6-methoxy-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-piperazine-1-carboxylicacid tert-butyl ester, and replacing 3-methylsulfonyl-benzenesulfonylchloride with the appropriate aryl- or heteroaryl-sulfonyl chloridesfollowed by de-protection using trifluoracetic acid or hot hydrogenchloride in ethanol, the following compounds were prepared:

-   4-(2-Fluoro-benzenesulfonyl)-6-methoxy-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    hydrochloride salt, MS: MH⁺ 406.-   4-Benzenesulfonyl-6-methoxy-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    hydrochloride salt, MS: MH⁺ 388.-   4-(2,3-Dihydro-benzo[1,4]dioxine-6-sulfonyl)-6-methoxy-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    hydrochloride salt, MS: MH⁺ 447.-   6-Methoxy-4-(naphthalene-1-sulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    trifluoroacetic acid salt, MS: MH⁺ 439.-   4-(2-Chloro-benzenesulfonyl)-6-methoxy-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    trifluoroacetic acid salt, MS: MH⁺ 423.-   4-(3-Chloro-benzenesulfonyl)-6-methoxy-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    trifluoroacetic acid salt, MS: MH⁺ 423.-   4-(5-Fluoro-2-methyl-benzenesulfonyl)-6-methoxy-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    trifluoroacetic acid salt, MS: MH⁺ 420.-   6-Methoxy-8-piperazin-1-yl-4-(toluene-2-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine,    trifluoroacetic acid salt, MS: MH⁺ 402.

Similarly, but replacing4-(6-chloro-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-piperazine-1-carboxylicacid tert-butyl ester with4-(6-fluoro-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-piperazine-1-carboxylicacid tert-butyl ester, and replacing 3-methylsulfonyl-benzenesulfonylchloride with the appropriate aryl- or heteroaryl-sulfonyl chloridesfollowed by de-protection using trifluoracetic acid or hot hydrogenchloride in ethanol, the following compounds were prepared:

-   6-Fluoro-4-(2-fluoro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    hydrochloride salt, MS: MH⁺ 394.-   4-Benzenesulfonyl-6-fluoro-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    hydrochloride salt, MS: MH⁺ 376.-   4-(2,3-Dihydro-benzo[1,4]dioxine-6-sulfonyl)-6-fluoro-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    hydrochloride salt, MS: MH⁺ 434.

Similarly, but replacing4-(6-chloro-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-piperazine-1-carboxylicacid tert-butyl ester with4-(6-tert-butyl-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-piperazine-1-carboxylicacid tert-butyl ester, and replacing 3-methylsulfonyl-benzenesulfonylchloride with the appropriate aryl- or heteroaryl-sulfonyl chloridesfollowed by de-protection using trifluoracetic acid or hot hydrogenchloride in ethanol, the following was prepared:

-   6-tert-Butyl-4-(2-fluoro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    hydrochloride salt, MS: MH⁺ 433.

Example 2

Synthesis ofN-[3-(8-piperazin-1-yl-2,3-dihydro-benzo[1,4]oxazine-4-sulfonyl)-phenyl]methanesulfonamide

3-Nitro-benzenesulfonyl chloride (122.9 mg, 0.55 mmol) was added insmall portions under nitrogen to an ice-cold solution of4-(3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-piperazine-1-carboxylic acidtert-butyl ester (161 mg, 0.504 mmol) and pyridine (88 mg, 1.11 mmol) indichiormethane (2 mL). After 0.5 hour at ambient temperature, water wasadded. The organic phase was separated, washed with saturated aqueoussolution of sodium bicarbonate (20 mL), dried (Na₂SO₄) and concentratedto give4[4-(3-nitro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl]-piperazine-1-carboxylicacid tert-butyl ester as an oil (260 mg). MS: MH⁺=505.

A solution of the crude material from Procedure a in ethanol (5 mL) washydrogenated at atmospheric pressure over 10% Pd/C (50 mg) for 0.5 hour.The catalyst was removed by filtration, and the filtrate wasconcentrated to give4-[4-(3-amino-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl]-piperazine-1-carboxylicacid tert-butyl ester as a white solid (150 mg). MS: MH⁺=475.

A solution of methanesulfonyl chloride (75 mg, 0.64 mmol) indichloromethane (0.5 mL) was added dropwise under nitrogen to anice-cold solution of the crude material obtained in Procedure b (145 mg,0.31 mmol) and triethylamine (65 mg, 0.65 mmol) in dichloromethane (2mL). After 1 hour at ambient temperature, water (2 mL) was added. Thelayers were separated. The organic phase was washed with water (2 mL),dried (Na₂SO₄) and concentrated to give4-[4-(3-dimethanesulfonylamino-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl]-piperazine-1-carboxylicacid tert-butyl ester as an oil (50 mg, 25%).

A solution of the above intermediate in tetrahydrofuran (1 mL) wastreated with 2N sodium hydroxide (1 mL). After 12 hours, ethyl acetatewas added (10 mL). The layers were separated, dried (Na₂SO₄) andconcentrated. De-protection as described in step 4 above gaveN-[3-(8-piperazin-1-yl-2,3-dihydro-benzo[1,4]oxazine-4-sulfonyl)-phenyl]-methanesulfonamide(25 mg, 30%) as a off-white powder. MS: MH⁺=453. M.p. 158.5-163.5° C.

Example 3

This example illustrates a method for producing Compounds of Formula Iusing the synthetic scheme outlined below:

Synthesis of8-bromo-4-(4-chloro-benzenesulfonyl)-6-methyl-3,4-dihydro-2H-benzo[1,4]oxazine

4-Chloro-benzenesulfonyl chloride (560 mg, 2.65 mmol) was added in smallportions under nitrogen to an ice-cold solution of8-bromo-6-methyl-3,4-dihydro-2H-benzo[1,4]oxazine (550 mg, 2.41 mmol)and pyridine (381 mg, 4.82 mmol) in dichloromethane (20 mL). After 12hours at ambient temperature, water was added. The layers wereseparated. The organic phase was washed with saturated aqueous solutionof sodium bicarbonate (20 mL), dried (Na₂SO₄) and concentrated to givethe title compound as a solid (820 mg, 84%). A sample was recrystallizedfrom ethanol. MS: M⁺=401. M.p. 143.0-145.1° C.

Similarly, the following compounds were prepared:

-   8-Bromo-4-(3,4-dichloro-benzenesulfonyl)-6-methyl-3,4-dihydro-2H-benzo[1,4]oxazine    as a white powder. MS: M⁺=435. M.p. 150-151° C.-   4-Benzenesulfonyl-8-bromo-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine.    MS: M⁺=387.-   8-Bromo-6-chloro-4-(2-chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine    as a white solid. MS: M⁺=422.-   8-Bromo-6-chloro-4-(2-fluoro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine    as a white solid. MS: M⁺=405.-   8-Bromo-6-chloro-4-(naphthalene-1-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine    as a white solid. MS: M⁺=437.-   8-Bromo-4-(3-chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine    as an oil which solidified upon standing.

Using the above procedure, but starting with8-bromo-2,2-dimethyl-3,4-dihydro-2H-benzo[1,4]oxazine (prepared byreducing 8-bromo-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one, which in turnwas prepared from 2-amino-6-bromophenol and 2-bromo-2-methylproprionylbromide via the procedure described by Van Hes et al., WO 01/14330) and2-fluorobenzenesulfonyl chloride,8-bromo-4-(2-fluorobenzenesulfonyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[1,4]oxazinewas obtained as a white solid. MP.: 108.0-110.1°.

In another variation of the above procedure,8-bromo-6-methyl-3,4-dihydro-2H-benzo[1,4]oxazine was replaced with4-bromo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene (obtained byreduction of 4-bromo-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one,which in turn was prepared by reaction of 2-amino-6-bromophenol with3-chloropropionyl chloride as described by Combs et al.; J. Med. Chem.;33; 380-386 1990). Reaction of4-bromo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene withbenzenesulfonyl chloride yielded9-benzenesulfonyl-4-bromo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepteneas a white solid, MS: M⁺=336.

Method A: Synthesis of4-(4-chloro-benzenesulfonyl)-6-methyl-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

A three neck flask was charged withtris(dibenzylideneacetone)dipalladium(0) (9.1 mg, 0.001 mmol, 2 mol %Pd), (±)-2,2′-bis(diphenylphosphino)-1,1-binaphthyl (15.5 mg, 0.025mmol, 5 mol %), and sodium-tert-butoxide (67 mg, 0.7 mmol) and flushedwith nitrogen. A solution of8-bromo-4-(4-chloro-benzenesulfonyl)-6-methyl-3,4-dihydro-2H-benzo[1,4]oxazine(201 mg, 0.5 mmol) and piperazine (129 mg, 1.5 mmol) in toluene (5 mL)was added. The mixture was heated to 95° C. and stirred for 18 hours.The mixture was cooled to room temperature, taken up in ethyl acetateand filtered. The organic phase was washed with water (2×20 mL) andextracted into 10% aqueous HCl (2×20 mL). The combined aqueous extractswere basified with solid potassium carbonate and extracted into ethylacetate (2×20 mL). The combined organic extract was dried (K₂CO₃),filtered and concentrated to give the title compound as an oil (163 mg,79.6%). The hydrochloride salt was prepared from ethanol-hydrogenchloride. MS: MH⁺=408. M.p. 147.9-152.9° C.

Similarly, using the appropriate aryl- and heteroaryl-sulfonylchlorides, the following compounds were prepared:

-   4-(3,4-Dichloro-benzenesulfonyl)-6-methyl-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine    as white powder. MS: MH⁺=442. M.p.257-261° C.-   4-(4-Chloro-benzenesulfonyl)-8-(3,5-dimethyl-piperazin-1-yl)-6-methyl-3,4-dihydro-2H-benzo[1,4]oxazine    as a off-white solid. MS: MH⁺=436. M.p. 171.8-185.8° C.

Similarly, using8-bromo-4-(2-fluorobenzenesulfonyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[1,4]oxazine,4-(2-Fluoro-benzenesulfonyl)-2,2-dimethyl-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazinewas prepared as hydrochloride salt. MS: MH⁺=406.

Similarly, using9-benzenesulfonyl-4-bromo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene,9-Benzenesulfonyl-4-piperazin-1-yl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptenewas prepared as a hydrochloride salt. MP.: 225.7-226.8.

Method B: Synthesis of4-benzenesulfonyl-6-chloro-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine

A three neck flask was charged withtris(dibenzylideneacetone)dipalladium(0) (6.4 mg, 0.007 mmol, 2 mol %Pd), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (10.8 mg, 0.017mmol, 5 mol %), and sodium tert-butoxide (47 mg, 0.48 mmol) and flushedwith nitrogen. A solution of4-benzenesulfonyl-8-bromo-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine (165mg, 0.35 mmol) and piperazine-1-carboxylic acid tert-butyl ester (71.1mg, 0.38 mmol) in toluene (2 mL) was added. The mixture was heated to95° C. and stirred for 12 hours. The mixture was cooled to roomtemperature, taken up in ethyl acetate, filtered and concentrated. Thecrude material was purified by flash chromatography on silica gel(eluting with hexane-ethyl acetate; 7:3, v/v) to give4-(4-Benzenesulfonyl-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-piperazine-1-carboxylicacid tert-butyl ester as an oil (129 mg, 75%). MS: MH⁺=494. The crudematerial was dissolved in ethanol (1 mL) and was treated with a solutionof 10% hydrogen chloride in ethanol (1 mL). The mixture was heated on asteam bath for 15 minutes. White crystals precipitated upon cooling toroom temperature. The solid was collected, washed with cold ethanol.Drying under vacuum gave4-benzenesulfonyl-6-chloro-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,hydrochloride salt as a white powder (90 mg, 73%). MS: MH⁺=394. M.p.202-205° C.

Similarly, the following compounds were prepared.

-   6-Chloro-4-(2-chloro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    hydrochloride salt as a white powder. MS: MH⁺=428. M.p.>250° C.-   6-Chloro-4-(3-chloro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    hydrochloride salt as a white powder. MS: MH⁺=428. M.p. 193.4-196.5°    C.-   6-Chloro-4-(2-fluoro-benzenesulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    hydrochloride salt as a white powder. MS: MH⁺=412. M.p. 194.8-204.5°    C.-   6-Chloro-4-(naphthalene-1-sulfonyl)-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    hydrochloride salt as a white powder. MS: MH⁺=444. M.p. 273.7-276.6°    C.

Similarly, but replacing piperazine-1-carboxylic acid tert-butyl esterwith [1,4]diazepane-1-carboxylic acid tert-butyl ester and4-benzenesulfonyl-8-bromo-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine with8-Bromo-4-(3-chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazinethe following compound was prepared:

-   4-(3-Chloro-benzenesulfonyl)-8-[1,4]diazepan-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine,    hydro chloride salt as a white powder. MS: MH⁺=408. M.p.    175.9-180.3° C.

Example 4

This example illustrates a method for preparing8-bromo-2,3-dihydro-benzo[1,4]oxazine.

A solution of 2-(2,6-dibromo-phenoxy)acetamide (9.3 g, 0.03 mol) intetrahydrofuran (100 mL) was heated to reflux and borane-dimethylsulfide(4.5 mL, 0.045 mL) was added in drops over a period of 15 min. After 3h, 20 mL of ethanolic hydrogen chloride (2M, 0.4 mol) was added. Thesolution was refluxed for 30 min. Upon cooling to ambient temperature awhite solid precipitated which was filtered and washed with diethylether (20 mL) to give 2-(2,6-dibromo-phenoxy)ethylamine, hydrochloridesalt (7.25 g, 73.3%). MS: MH⁺=294. M.p. 249.7-252.3° C.

A three neck flask was charge withtris(dibenzylideneacetone)dipalladium(0) (0.37 g, 0.0004 mol, 2 mol %Pd), (O) racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.64 g,0.001 mol, 5 mol % Pd), and sodium tert-butoxide (2.7 g, 0.028 mol) andflushed with nitrogen. A solution of 2-(2,6-dibromo-phenoxy)ethylamine(6 g, 0.02 mol) in toluene (50 mL) was added. The mixture was heated to95° C. and was stirred for 12 h. The mixture was cooled to roomtemperature, taken up in ethyl acetate, filtered and concentrated. Thecrude material was purified by flash chromatography on silica gel(eluting with hexane-ethyl acetate; 7:3, v/v) to give8-bromo-3,4-dihydro-2H-benzo[1,4]oxazine as an oil (275 mg, 48%). Thehydrochloride salt was prepared from ethanol-hydrogen chloride. MS:MH⁺=214. M.p. 184.1-195.4° C.

The synthesis of 6-bromo-3,4-dihydro-2H-benz[1,4]oxazine is reported inthe following reference. Nugiel, David A.; Jacobs, Kim; Cornelius,Lyndon; Chang, Chong-Hwan; Jadhav, Prabhakar K.; et al; J. Med. Chem.;40; 10; 1997: 1465-1474. 6-bromo-3,4-dihydro-2H-benz[1,4]oxazine may beused in the procedures of Example 1 and 2 to provide the correspondingcompounds of Formula I.

Example 5

This example illustrates in vitro radioligand binding studies ofCompound of Formula I.

The binding activity of compounds of this invention in vitro wasdetermined as follows. Duplicate determinations of ligand affinity aremade by competing for binding of [³H]LSD in cell membranes derived fromHEK293 cells stably expressing recombinant human 5-HT6 receptor. Thiscell line was prepared by the method described by Monsma et al.,Molecular Pharmacology, Vol. 43 pp. 320-327 (1993).

All determinations were made in assay buffer containing 50 mM Tris-HCl,10 mM MgSO₄, 0.5 mM EDTA, 1 mM ascorbic acid, pH 7.4 at 37° C., in a 250microliter reaction volume. Assay tubes containing [³H] LSD (5 nM),competing ligand, and membrane were incubated in a shaking water bathfor 60 min. at 37° C., filtered onto Packard GF-B plates (pre-soakedwith 0.3% PEI) using a Packard 96 well cell harvester and washed 3 timesin ice cold 50 mM Tris-HCl. Bound [³H] LSD was determined as radioactivecounts per minute using Packard TopCount.

Displacement of [3H]LSD from the binding sites was quantified by fittingconcentration-binding data to a 4-parameter logistic equation:${binding} = {{basal} + \left( \frac{{B\quad\max} - {basal}}{1 + 10^{- {{Hill}({{\log{\lbrack{ligand}\rbrack}} - {\log\quad{IC}_{50}}}}}} \right)}$where Hill is the Hill slope, [ligand] is the concentration of competingradioligand and IC₅₀ is the concentration of radioligand producinghalf-maximal specific binding of radioligand. The specific bindingwindow is the difference between the Bmax and the basal parameters.

Using the procedures of Example 5, compounds of Formula I were testedand found to be selective 5-HT6 antagonists.

Example 6

The cognition-enhancing properties of compounds of the invention may bein a model of animal cognition: the object recognition task model.4-month-old male Wistar rats (Charles River, The Netherlands) were used.Compounds were prepared daily and dissolved in physiological saline andtested at three doses. Administration was always given i.p. (injectionvolume 1 ml/kg) 60 minutes before T1. Scopolamine hydrobromide wasinjected 30 minutes after compound injection. Two equal testing groupswere made of 24 rats and were tested by two experimenters. The testingorder of doses was determined randomly. The experiments were performedusing a double blind protocol. All rats were treated once with each dosecondition. The object recognition test was performed as described byEnnaceur, A., Delacour, J., 1988, A new one-trial test forneurobiological studies of memory in rats. 1: Behavioral data. Behav.Brain Res. 31, 47-59.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

1-35. (canceled)
 36. A method for treating a CNS disease state in asubject, said method comprising administering to said subject atherapeutically effective amount of a compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein m is an integerfrom 0 to 3; each of n and p is independently an integer from 2 to 3; Yis —S(O₂) or —S(O₂)—N(R¹⁰)—, where R¹⁰ is hydrogen or lower alkyl; Z¹ isCH or N; each of R¹ and R² is independently hydrogen or alkyl, or R¹ andR² together with the carbon to which they are attached may form acarbocyclic group with 3 to 6 ring atoms; R³ is alkyl, aryl, haloalkyl,heterocyclyl, or heteroaryl; each R⁴ is independently halo, alkyl,haloalkyl, alkoxy, cyano, —SO₂R^(a), —C(═O)—NR^(b)R^(c),—SO₂—NR^(b)R^(c), —SR^(b), —N(R^(b))—C(═O)—R^(c)—C(═O)—, or—N(R^(b))—SO₂—R^(a),  where each R^(a) is independently alkyl orhaloalkyl, and each of R^(b) and R^(c) is independently hydrogen, alkyl,or haloalkyl; each of R⁵, R⁶, R⁷, and R⁸ is independently hydrogen oralkyl; and R⁹ is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl or benzyl;or R⁹ and one of R⁵, R⁶, R⁷, or R⁸ together with the atoms to which theyare attached form a heterocycloamino ring with 5 to 7 ring atoms. 37.The method of claim 36, wherein the disease state comprises psychoses,schizophrenia, manic depressions, neurological disorders, memorydisorders, attention deficit disorder, Parkinson's disease, amyotrophiclateral sclerosis, Alzheimer's disease and Huntington's disease.
 38. Amethod for treating memory disorders or Alzheimer's disease in asubject, said method comprising administering to said subject atherapeutically effective amount of a compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein m is an integerfrom 0 to 3; each of n and p is independently an integer from 2 to 3; Yis —S(O₂)— or —S(O₂)—N(R¹⁰)—, where R¹⁰ is hydrogen or lower alkyl; Z¹is CH or N; each of R¹ and R² is independently hydrogen or alkyl, or R¹and R² together with the carbon to which they are attached may form acarbocyclic group with 3 to 6 ring atoms; R³ is alkyl, aryl, haloalkyl,heterocyclyl, or heteroaryl; each R⁴ is independently halo, alkyl,haloalkyl, alkoxy, cyano, —SO₂R^(a), —C(═O)—NR^(b)R^(c),—SO₂—NR^(b)R^(c), —SR^(b), —N(R^(b))—C(═O)—R^(c), —C(═O)—R^(b), or—N(R^(b))—SO₂—R^(a),  where each R^(a) is independently alkyl orhaloalkyl, and each of R^(b) and R^(c) is independently hydrogen, alkyl,or haloalkyl; each of R⁵, R⁶, R⁷, and R⁸ is independently hydrogen oralkyl; and R⁹ is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl or benzyl;or R⁹ and one of R⁵, R⁶, R⁷, or R⁸ together with the atoms to which theyare attached form a heterocycloamino ring with 5 to 7 ring atoms.
 39. Acompound of the formula:

or a pharmaceutically acceptable salt thereof, wherein: R³ is alkyl,aryl, haloalkyl, heterocyclyl, or heteroaryl; and R⁹ is hydrogen, alkyl,cycloalkyl, cycloalkylalkyl or benzyl.
 40. The compound of claim 39,wherein R³ is aryl or heteroaryl.
 41. The compound of claim 40, whereinR⁹ is hydrogen or alkyl.
 42. The compound of claim 41, wherein R³ isoptionally substituted phenyl.
 43. The compound of claim 42, wherein R⁹is hydrogen or methyl.
 44. The compound of claim 43, wherein R³ isphenyl, 2-fluorophenyl, 2-chlorophenyl, 3,4-dichlorophenyl,4-chlorophenyl, 3-chlorophenyl, 4-methoxyphenyl, 3,5-dichlorophenyl,2,3-dichlorophenyl, 2,6-dichlorophenyl, 2,4-dichlorophenyl,3-methanesulfonylaminophenyl, 2-methanesulfonylphenyl,2-carbamoylphenyl, 3-methanesulfonylphenyl, 4-methanesulfonylphenyl,3-fluorophenyl, naphthylene-1-yl, 2,4-difluorophenyl, 2-cyanophenyl,2-chloro-4-fluorophenyl, 5-fluoro-2-methylphenyl, 5-chloronaphthyl,naphthylene-2-yl, 4-fluoro-2-methylphenyl, 2-hydroxyphenyl,2-methoxyphenyl, 4-(piperazin-1-yl)-phenyl, or2,3-dihydrobenzo[1,4]dioxinyl
 45. The compound of claim 41, wherein R³is optionally substituted heteroaryl.
 46. The compound of claim 45,wherein R³ is quinolin-8-yl, thiophen-2-yl, 5-chlorothiophen-2-yl,isoquinolin-5-yl, 4-(Benzo[1,2,5]thiadiazole-4-yl,1-methyl-1H-imidazole-4-yl, or 4-(Benzo[1,2,5]oxadiazole-4-yl.
 47. Thecompound of claim 43, wherein R³ is 2-halophenyl.
 48. The compound ofclaim 43, wherein R³ is 2-fluorophenyl.
 49. The compound of claim 48,wherein R⁹ is hydrogen.
 50. A composition comprising: (a) atherapeutically effective amount of a compound of claim 39; and (b) apharmaceutically acceptable carrier.